Method of destroying lactobacilli em-



United States Patent fifice 3,003,915 Patented Oct. 10, 1961 3,003,915METHOD OF DESTROYING LACTOBACILLI EM- MONO (TETRADECYLAMINE) MALO- PaulM. Borick, Cranford, N.J., and Martin Daniel Bratt, Edgewood, Md.,assignors to Bristol-Myers Company, New York, N.Y., a corporation ofDelaware No Drawing. Filed Dec. 11, 1959, Ser. No. 858,857 1 Claim. (Cl.167-22) This application relates to germicidal compositions and moreparticularly to germicidal compositions containing amine salts ofmalonic acid. The germicidal salts of this invention have the genericformula:

1 R-IYI (C 31340 4) wherein R is an alkyl radical having from about 12to about 16 carbon atoms; R is hydrogen or an alkyl radical having from1 to 6 carbon atoms; R is hydrogen or an alkyl radical having from 1 to6 carbon atoms and n is 1 or 2.

Most germicides suffer from a variety of defects such as: specificity toonly certain types of microorganisms; inactivation when in contact withorganic matter; inactivation with hard water, i.e., Water containingrelatively high concentrations of calcium or magnesium salts; having anarrow pH sensitivity; having an odor; or causing a discoloration ofclothing and other materials with which the germicide comes in contact.Thus, penicillin, sulfonamides and certain antibiotics are specific togram positive bacteria. Other germicides such as fatty acids, salts offatty acids, salicylates and benzoates are specific to the fungi. Thefatty acids also have a very perceptible odor. Germicides such asgentian violet and copper-8- quinolinolate impart a color to germicidalcompositions and materials which come in contact with the compositionssuch as clothing. Only a limited number of germicides are effectiveagainst gram negative bacteria and only a few of the germicides whichare effective against the gram negative bacteria possess a broadgermicidal spectmm.

It has now been found that the malonic acid salts of certain alkylamines have good activity against a wide variety of microorganisms suchas the gram positive bacteria, gram negative bacteria and the variousfungi. In addition, these salts are not inactivated by organic matter orhard water. They do not possess an undesirable perceptible odor; do notcause discoloration of clothing; and are active over a broad pH range,e.g., pH of 2 to 12.

The amines employed for producing the germicidal salts of this inventionare alkyl amines and can be primary, secondary or tertiary amineswherein one alkyl chain contains from about 12 to about 16 carbon atomsand preferably 14 carbon atoms. The remaining valences of the nitrogenatom of the alkyl amine reactant are satisfied by hydrogen or alkylradicals containing from 1 to 6 carbon atoms. Amine salts of malonicacid with less than about 12 carbon atoms, e.g., 7 or 8 carbon atoms inthe long chain alkyl group of the amine portion of the salt areirritating to the skin and do not possess the high germicidal activityof those having 12 to 16 carbon atoms in the alkyl chain. Amine saltswith more than about 16 carbon atoms, such as 22 carbon atoms, do nothave the high order of activity of the shorter chain alkyl radicalscontaining about 12 to 16 carbon atoms. Illustrative of the germicidalsalts there can be mentioned: mono (dodecylamine) m'alonate; di(dodecylamine) malonate; mono (tridecylamine) malonate;

mono (tetradecylamine) malonate; di (tetradecylamine) malonate; mono(pentadecylamine) malonate; di (pentadecylamine) malonate; mono(hexadecylamine) malonate; di (hexadecy-lamine) malonate; mono(N,N-dimethyldodecylamine) malonate; di (N,N-dimethyldodecylamine)malonate; mono (N,Ndiethyltetradecylamine) malonate; di(diethyltetradecyl-amine) malonate; mono('N-ethyl-N-propyl-tetradecylamine) malonate; di(N-methyltetradecylamine) malonate; and di (N,N-dibutylpentadecylamine)malonate. The germicidal salts employed are those wherein either one orboth of the two carboxylic acid groups of the dibasic acid have beenneutralized. Of course, compositions which contain a mixture of thesalts can also be employed. The chemical formula for mono(tetradecylamine) malonate and di (tetradecylamine) malonaterespectively, can be represented as: C H NH -HOOC-CH COOH and (C H NH'HOOC-CH --COOH. For convenience, in the nomenclature of these salts,the portion of the salt possessing the amine compound is referred to asthe amine portion of the salt, e.g., in the case of the mono(tetradecylarnine) vmalonate it is the portion to the left of thebonding dot. The chemical formula for the mono and di (tetradec-ylamine)malonate can also be expressed respectively as The germicidal salts ofthis invention can be prepared by simply dissolving malonic acid and theamine in an organic polar solvent at room temperature. Heating themixture of polar solvent, amine and dibasic acid at slightly elevatedtemperatures such as 40 C. to 60 C. aids in solubilizing the mixture.The salts can be precipitated from their solution in the polar solventby cooling the solution to a temperature of about 1 to 10 C. or addingether to the solution. The solid germicidal salts are then recoveredfrom the reaction medium by conventional means such as by filtration.

EXAMPLE 1 This example shows the preparation of mono (tetradecylamine)malonate. The salt was prepared by mixing solutions of 0.1 mol oftetradecylamine (C H N) and 0.105 mol of malonic acid (C H Oin'jafrninimum quantity of ethanol as a solvent at room temperature. Theslight excess of acid was used to prevent formation of the di(tetradecylamine) salt. The salt precipitated upon addition of ether(about ten times asmuch ether was added as compared to the ethanol usedas a solvent). The reaction mixture was then filtered to recover thesalt. The salt was subsequently recrystallized from acetone. The yieldof mono (tetradecylamine) malonate was about 84% based on the aminereactant. The salt was white in color and had a melting point of 95.5 C.to 97 0.; molecular weight of 309 (calc. 317) and nitrogen analysis of4.4% (calc. 4.4%

The germicidal salts of this invention can be used in their pure formfor their germicidal activity or preferably by formulating germicidalcompositions wherein the germicidal salts are used in germicidallyetfective amounts such as from about 0.05% to about 5% of the entirecomposition and preferably from about 0.1% to 1% with the remaining ormajor portion of the composition comprising conventional germicidaladjuv-ants or carriers. Thus, they can be formulated as solutions,suspensions, emulsions, or powders with the conventional carriers.

The germicidal compositions of the invention may also take the form ofpreparations suitable -for dispensing as aerosols, liquids or foams fromconventional, resilientwalled or pressurized containers. For suchpurposes, the compounds may be incorporated in non-solvent suspensionsor emulsions or they may be dissolved in suitable solvents as analcohol, acetone or the like. If these are to be dispensed frompressurized containers, conventional propellants may be used such as thevarious haloalkanes, hydrocarbon gases, nitrogen, carbon dioxide, etc.When desired, film-forming materials can also be incorporated in thecompositions. The film-forming materials can be the self-supporting typeof film-formers such as cellulose derivatives, natural or syntheticlacquers, etc. or they can be selected from non-self-supportingfilm-forming materials such as silicones.

The germicidal compounds of the invention can also be formulated for usein the form of powders. Conventional pulverulent carriers can beutilized such as starch, talc, etc. For example, a suitable antimycoticpowder can be prepared in accordance with the following formulation.

The germicidal activities of certain of the contemplated compounds areillustrated and compared to those of some closely related substances inTable 1, wherein the activities are given, in milligrams percent (mg. asthe minimum concentration necessary to inhibit growth of themicroorganisms against which the compounds were tested. (One mg.percent=1 mg. of the compound being tested per 100 ml. of solutlon orparts per million).

Table 1 Mono Mixed Mono Mono (tetratetra- (tetra- (laurylTetradeclydecyldecyltrisdecylamine) amine amine) methylamine iumaratemalomalonate amine) palmitate mates 1 malonate S. aureus 1. 25 0. 6 0.30. St. f 1. 0.3 0. 6 1. 25 20 2.5 0.6 0.3 1.25 20 L 1. 25 0. 07 0.00150. 15 1. 25 0. 3 0. 07 0. 6 1. 25 1. 25 10 10 5.0 10 20 0.6 0.15 0.6 0.620 0.6 0.3 0.3 0.15 10 10 5.0 10 10 20 A. aeragenes 10 0. 6 1. 25 5 20L. delbrueckii 0.07 0.0015 0.0015 0. 3 10 M. gypseum 0. 3 0.3 20 0.3 20T. mentagrophytes. 0.3 0.6 1.25 25 20 SJU hose 10 0.6 1.25 2.5 20 S. (11us 0.6 0.15 0.3 0.15 20 B. ammoniaqenes" 0. 6 0. 07 0.3 1.25 20 P. ovale0. 3 0. 15 1. 25 0.15 20 1 The mixture contained about equal parts ofthe mono and di (tetradeeylamine) malonate.

It can be seen from the data of Table 1 thatthe malonate salts arehighly effective germicides, particularly against gram negativeorganisms and lactobacilli. Also, it can be seen from Table 1 that theamine salts of the malonates are more effective than the amine salts ofclosely related compounds such as palmitic acid or fumaric acid. H

The germicidal salts of this invention canalsobe employed aspreservatives and antifungal agents by incorporating them in materialsnormally susceptible to attack by microorganisms. Illustratively theycan. be incorporated in paints, e.g., antifouling marine paints, as wellas in adhesives and textile sizes. They can also be incorporated inarticles of molded plastic materials, such as synthetic resins,cellulose derivatives and the like whereby they confer on the moldedarticles a rcsistance to attack by various microorganisms such as thefungi. The salts of this invention can also be used as fungicidal agentson garden plants, such as tomatoes, wherein they can be admixed withconventional carriers such as talc and applied to plants.

What is claimed is:

A method for inhibiting the growth of lactobacilli which comprisesapplying to said lactobacilli a germicidally effective quantity of mono(tetradecylamine) malonate.

References Cited in the file of this patent UNITED STATES PATENTS1,873,732 Adams Aug. 23, 1932 2,218,181 Searle Oct. 15, 1940 2,779,741Cross n Jan. 29, 1957 OTHER REFERENCES King: US. Dept. Agr., HandbookNo. 69, page 221 (May 1954).

